CZ454090A3 - Pharmaceutical preparations for preventing and/or treating myocardial heart attack or brain apoplexy of mammals - Google Patents

Abstract

There are disclosed combination products useful for the treatment and/or prevention of a first or recurrent myocardial infarction or a first or recurrent stroke. Said combination products comprise low doses of an oral anticoagulant, preferably warfarin and platelet inhibiting agents, including non-steroidal antiinflammatory agents and preferrably aspirin.

Description

Pharmaceutical infarction or means for preventing and / or treating myocardial stroke in mammals

Technical field

The invention relates to pharmaceutical compositions for the prevention and / or treatment of myocardial infarction or stroke in mammals. These are combination products that contain small doses of oral anticoagulants and inhibitors of clotting and blood adhesion.

BACKGROUND OF THE INVENTION

Recent findings to understand the pathogenic factors leading to acute coronary ischemic syndromes of unstable angina, myocardial infarction and ischemic sudden death and acute cerebrovascular ischemic syndromes such as transient ischemic seizures and strokes have shown the importance of the two compounds, namely acetylsaline and acetylsaline to prevent and / or treat these symptoms. Recently, the importance of antithrombotic therapy with high doses of acetylsalicylic acid in unstable angina pectoris has been conclusively demonstrated by two random, double-blind, placebo-controlled trials. See, in particular, Lewis et al. Protective Effects Of Aspirin Against Acute Ilyocardial Infarction And Death In Men With Aspirin; the results of the study in cooperation with the Veterans Association _; published in the New England Journal of Medicine, 309: 396 (1933), and in Cairns et al. 1985). Also, the most recent results of several studies suggest that long-term high-dose oral anticoagulant therapy may reduce the recurrence rate of myocardial infarction by about 20 ΐ [Fustar et al. (1983) Perspective Insights into the Pathogenesis of Acute Ischemic Syndromes, 77, No. 6, pp. 1213-1220].

Since commercially available pharmaceutical products are contraindicated. to use an isolated inhibitory effect either on the clotting and adhering effect of blood or on the formation of thrombi; a combination of agents that inhibit both the aggregation / adhesion effect and the trmbus formation at the same time, an advantage in better efficacy when used in smaller doses than when using single agents. Although acetylsalicylic acid can prevent ischemic cardiac cases that are caused by coronary artery disease, and oral anticoagulants can protect against both ischemic cardiac cases and the resulting cerecral embolism due to ventricular trcmb, the best combination can be achieved in small doses ^ ^U3 ter V., Halperin JK (1939) The Nav; England Journal of Medicine,

February 9, 1989, pp. 392-394].

Traditionally, the concomitant use of warfarin and acetyisaiicic acid (aspirin) at high doses has been relatively high in medical circles. This was based on the medical literature reporting the adverse clinical and pharmacological effects of both drugs at high doses, the clinical tendency of acetylsalicylic acid to cause, at high doses, gastric mucosal erosion / ulceieration at dosing with oral anticoagulant (warfarin) to a widespread gastrointestinal incidence (GI) bleeding in high dose combination. Acetylsalicylic acid also acts synergistically with warfarin from a pharmacological point of view, resulting in an increase in prothrombin levels in a time trial for a given dose of warfarin. In light of the latest advances in the study of acute coronary syndromes and the recognition of the individual benefits that acetylsalicylic acid (?, SK) with warfarin acts medicinally and / or prophylactically against these syndromes, there is a need for a combination product containing an oral anticoagulant such as warfarin; an anti-agglomeration and anti-sticking agent of blood components such as ASK or a non-acetylsalicyclic non-steroidal anti-inflammatory agent at a low dose ratio. The combination makes it possible to use doses which are less than those commonly considered to be therapeutic in the medical literature, in other words, those which promote the beneficial effects of both side-effect agents in conjunction with the simultaneous administration of large doses of both. reagents.

taking into account commonly accepted standards

Existing drawbacks are eliminated from the predominant pharmaceutical compositions of this section.

SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions for preventing and / or treating myocardial infarction or stroke in mammals. SUMMARY OF THE INVENTION The pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier and a combination of active ingredients consisting of warfarin or its salts, methacrylate.

0.5 and 10 mg,

an anticoagulant component formed in a delivery amount that inhibits the clumping and adhesion function of the blood selected from the group consisting of

a) acetylsalicylic acid contained in an amount of 10 to 500 mg,

b) piroxicam contained in an amount of 5 to 50 mg,

c) indomethacin contained in an amount of 20 to 100 mg;

d) aaproxen contained in an amount of 20 to 100 mg;

e) droxicam contained in an amount of 20 to 100 mg,

f) diclofenac in a dosage amount of 20 to 100 mg;

g) sulfinpyrazone contained in an administration amount of 20 to 100 mg

h) ticlopidine contained in an amount of 100 to 750 mg. The anticoagulant component and the agent that inhibit blood clotting and adhesion functions may preferably be coated with an enteric or sustained release polymer, or both, wherein the enteric release polymer is selected from the group consisting of:

cellulose acetate phthalate; and

b) the methacrylic acid copolymer and the sustained release polymer are selected from the group consisting of

(a) methacrylic ester copolymer,

(b) ethylcellulose soluble in an organic solvent,

(c) ethylcellulose soluble in an aqueous solvent;

(d) hydroxypropylcellulose;

(e) hydroxypropylethylcellulose; and

f) hydroxypropylmethylcellulose, the warfarin polymer being hydroxypropylmethylcellulose, of which 2 wt. the solution has a viscosity of less than 2 Pa.s.

Although acetylsalioyl acid is a preferred inhibitory agent against the clotting and adhesion functions of blood in the pharmaceutical compositions of the present invention, the use of K-α and β-oxyl is also contemplated. . other non-steroidal non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit platelet aggregation and adhesion, such as ibuprofen, naproxen, sulindac, indomethacin, mefenamt, droxicam, diclofenac, sulfinpyrazone, and pircxicam, to the extent of this invention. Among the non-acetylsalicylic acid nonsteroidal anti-inflammatory drugs, a preferred embodiment of the present invention comprises warfarin and pircxicam, commercially available from Pfizer under the designation Feldene®, since piroxicam exhibits anti-clotting and anti-sticking effects when dosed once daily. The combination of piroxicam and warfarin preferably contains warfarin in a releasable amount of about 0.5 to 10 mg and piroxicam in a releasable amount of about to about 50 mg. Even more preferably, the combination could comprise warfarin in a releasable amount of about 1 to 7.5 mg and piroxicam in a releasable amount of ae. 10 to 40 mg. A most preferred embodiment comprises warfarin in a releasable amount of about 1 to 5 mg and piroxicam in a releasable amount of about 10 to 20 mg.

Other embodiments of the invention include the following

and drugs in the following listed Qty mg warfarin: Indomethacin, 20 to 100 mg, Naproxen, 20 to 100 mg, Droxicam, 20 to 100 mg, Diclofenac, 20 to 100 mg, Sulfinpyrazone, 20 to 100 mg. More preferably, if they are: above z s t v i t h a. 5 a ≥ 50 mg a warf ·

7, with mg. A most preferred embodiment of the non-acetylsalicylic acid drug and warfarin comprises the above-mentioned NSAIDs in an amount of -a-3 and 25 to 75 mg and warfarin in an amount of as-i 1 to 5 mg.

Another embodiment of the invention includes another agglomeration and adhesion inhibiting compound or thromboxane, such as ticlopidine, in combination with warfarin. Anti-adherence inhibitors such as ticlopidine are not associated with gastrointas final irritation, which may induce acetylsalioyl acid and other non-steroidal anti-inflammatory agents, and therefore, an acceptable dosage form can be achieved with respect to the course of gastrointestinal problems such as ulceleration. In addition, such a combination may be useful in a patient who is sensitive to acetylsalicylic acid or other non-steroidal anti-inflammatory agents. Preferably, such a combination comprises warfarin in a releasable amount of about 0.5 to 10 mg and ticlopidine in a releasable amount of about 100 to 750 mg. More preferably, the combination contains warfarin in a release amount of about 1 to 7.5 mg and ticlopidine in an amount of at least 200 to 600 mg. A most preferred embodiment comprises warfarin in an amount of about 1-5 mg and ticlopidine in an amount of about 250-500 mg.

Other inhibitory agents, anti-sticking due to aggregation or adueze such as thromboxane - ^ - receptor antagonists and thromboxane-A2-synthetase inhibitors ^_, may also be used in this invention.

The combination products of the invention may be in any dosage form known to those skilled in the art, for example in the form of one or more layered tablets, capsules, caplets, liquids or suppositories. Preferred dosage forms are tablets, capsules and caplets. These preferred dosage forms can be prepared by methods well known to those skilled in the art and described in Remington®. Pharmaceutical Sciences (1935), 17th edition, Osol, a standard reference in the art.

Due to the nature of the preferred compounds of the invention, i.e. warfarin and acetylsalicylic acid, there is the possibility of a chemical interaction between warfarin and acetylsalicylic acid, which are in a single dosage form. This possibility is exemplified by the results of experiments carried out for the compatibility of both substances; in this case, azetylsalicylic acid - υ - and sodium warfarin were mixed in a ratio of 1 part of warfarin sodium to d0 parts by weight of acetylsalucylic acid and soaked at room temperature at 60 ° C or at light intensity □ 4.5 candelas (cd) per area 1 dm \ The results are recorded as the average percentage of preservation and are given in Table I. The parentheses are the - deviations.

Table I

Stability of acetylsylicylic acid (ASK) and sodium warfarin (US) in solid form after one week

Conditions ASK stored alone ASK mixed with US in proportion 80: 1 , 1'o 5 iTi 3. with ASIA 1: chaný v perně: 30 Deň: 18 ° C 101.1 (0.5) 100.5 (0.5) 99.6 (1.8) 60 ° C 99.8 (1.6) 76.5 (2.9) 7 Ό Q (3,31) 64.5 cd / dm ^ 100.9 (1.0) 94.1 (2.7) and ie 4 / O (9.5)

Therefore, preferred dosage forms of the invention are formulated such that physical contact between warfarin and acetylsalicylic acid is minimized. In order to minimize contact between warfarin as one component and ASK as the other component, one embodiment of the present invention relates to a combination product in which the ASX component is enteric coated. In the enteric coating of ASK, it is possible to achieve as close contact as possible between the two active ingredients and also to control the release of ASK in the gastrointestinal tract so that ASK is not released in the stomach but rather in the intestines. The formulation thus formulated further reduces the risk of ASK-related gastrointestinal side effects, since ASZC is present not only in a small dose but releases less in the gastrointestinal tract as it is enteric coated.

Another embodiment of the invention relates to a combination product in which acetylsalicylic acid (ASK) is coated with a material that permits sustained release throughout the gastrointestinal tract and also serves to limit warfarin contact with ASK. In addition, an enteric coating can be additionally coated with a sustained-release ASK such that it is released only in the intestine.

Another solution to this problem is to formulate a combined statement in which the ASX component is coated with a polymer that permits release and / or in the intestine, and warfarin particles or granules thereof are also coated with a polymer such as low viscosity hydroxypropylmethylcellulose (HPZIC), or other suitable materials known in the art to further separate the active ingredients from one another. Similarly, perfargarine can be dry granulated with suitable excipients and the resulting granules are then coated with HPMC. Coating the warfarin component provides an additional barrier to ASX interaction.

The dosage forms of the present invention in which the ASX component is in an enteric coating may be in the form of tablets wherein the coated ASX and warfarin are mixed together and then compressed to form a mixture without proceeding.

The coated ASX compresses into one layer of the tablet and then the v / arfarin into the next layer of the tablet. Optionally, one or more placebo layers may be used to separate the two layers further from each other, wherein the placebo layer is between the warfarin layer and the ASX layer.

The dosage forms of the invention may additionally be in the form of capsules in which the ASX component is compressed into a tablet, or the ASX component is preferably in the form of several micro-tablets, particles, granules or other particles which are then enteric coated. These enteric coated microtablets, particles and granules are then placed into a capsule or compressed into a capsule together with the warfarin granulate. Conversely, the warfarin component may be formulated into a tablet or microtablet and placed in a capsule together with a powder mixture consisting of ASX that is released enterically or sustainably and is present in the form of coated particles or granules.

Another embodiment of the present invention includes a sustained release dosage form in which the ASX is formulated to be released for 2 to 12 hours. Alternatively, the .asx can be adjusted for release for 3 to 12 hours only in the intestine.

The compositions of the invention may contain, in addition to the active ingredients, suitable excipients which include, but are not limited to: lubricants such as magnesium stearate, stearic acid, sodium stearyl fumarate and hydrogenated vegetable oils; wetting agents such as lactose, microcrystalline cellulose, dextrosis, starch and dicalcium phosphate; a glidant such as colloidal silicon dioxide; and disintegrants such as sodium starch glycolate and croscarmellose sodium. The use of such excipients is well known to those skilled in the art of formulating pharmaceutical compositions.

In the following examples, various mixtures of warfarin and acetylsalicyl combination products are described. These formulations are intended to be exemplary only, as it will be understood that variations can be made by one skilled in the art.

I. immediate release of ASX in the intestine

1. Enterically coated with ASK / warfarin sodium

The following procedure may be used to provide a product that delivers the drug directly to the intestine, where it is immediately released, as well as physical separation of sodium and ASI warriors.

A. Enterically coated ASK in admixture with warfarin sarcoma

The ASK particles, granules or granules are enterically coated with a polymer dissolved in a solvent or water using a fluidized bed process, a bath coating process, a solids process, or other methods well known in the art. Examples of enteric coatings that can be used include cellulose acetate phthalate (Aquateris®,

EMC Corp.) and various methacrylic acid copolymers (Eudragit®

L30E, Eudragit® E or Eudragit® 5, available from Rohm

And other enteric coating materials known in the art. Eudragiin * L3OD can be used alone or in combination β) with Eudragitr * f, _,. , -,.

I30D (methacrylate ester xopolymer obtainable from Rohm Pharma). For cases where the coating process is carried out using water as the solvent, a thin coating of hydroxypropylmethylcellulose may be used. The coating layer serves to limit the contact of ASK with warfarin in a dosage form, in addition to aiding dietary release. The coated granules, granules and beads are then mixed with sodium warfarin and suitable excipients, and the mixture is either encapsulated. The following are examples of formulation of this type.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 Entsrically coated AS mixed with warfarin sodium

Component Amount (mg) per dosage unit.

ASX coated with 9 to 25% by weight (6)

Eudragit ** L 3GD

Warfarin socny

Microcrystalline cellulose Sodium glycolate starch Colloidal silicon dioxide Sodium stearyl fumarate

549.45 to δδο, δβ (500 mg active)

1.0

82.74 to 199.95

32.0

1.6

10.0

Total 800.0 mg

Prior to weighing, all components are sieved through a suitable sieve as required. All the components were weighed and warfarin sodium was mixed with colloidal silica, sodium starch glycolate and one half of microcrystalline cellulose, and the mixture was stirred for about 15 minutes in a double-shell mixer. The second half of sodium stearyl fumarate is then added and mixed for about 3 minutes.

This mixture was crushed using 1.27dpm flat bumpers and then ground. ASX was added to the remaining microcrystalline cellulose and stirred for 15 minutes. This mixture was added to warfarin sodium as a granulate and mixed for about 7 minutes.

The remaining sodium stearyl fumarate is then added, the mixture is stirred for 3 minutes and compressed into tablets. It should be noted that the microcrystalline cellulose for such a formulation is added in an amount such that the total dose weight is 300.0 mg.

Example 2

Lntencx in povx2 ·:

in;

; mosi

- / arrannea socav.

Component

Xa (mg) aa dosage unit

ASZC coated with 2.4 wt. L30D (2 wt% hydroxypropyl methylcellulose on the coating) starch

Warfarin sodium

Z-cicrocrystalline cellulose Sodium glycolate starch .Mloic. Magnesium stearate

120.52 (160 mg active) 100.16

1.0

126.0

20.0

1.0

1.25 «external mg

Prior to weighing, all components are sieved through a suitable sieve as required. All components were weighed and sodium warranarin mixed with colloidal silica gel, glyclate

2 ~ 1 of sodium and one half of the microcrystalline cellulose in a double-jacketed tray and mixed for about 15 minutes. One half of magnesium stearate is added and the mixture is stirred for about 2 minutes. Slug this blend using a l cm 27j _of flat-face punches and then milled. ASX (acetylsalicylic acid) was added to the remaining microcrystalline cellulose and the mixture was stirred for about 15 minutes. This mixture was added to granulated sodium warfarin and stirred for about 7 minutes. The remainder of the magnesium stearate is then added, mixed for about 3 minutes, and the resulting mixture is compressed into tablets or alternatively placed in capsules.

Using this recipe and the manufacturing process, 11.1 cm tablets are produced having a hardness of 3 to 10 Stroag-Cobb units (SCJ). Solubility tests are performed for both drugs according to the solubility tests for enteric coated A.3ZZ tablets and warfarin sodium tablets as described in United States Pharmacopoeia / Kational Formula (USP / XF) XVII.

For ASX, solubility was determined by placing the tablets in baskets that rotate at 100 mediums using a 750 mC test hour, then adding 250 rpm. As a hCl (37 [deg.] C.) for orbital two

Sodium phosphate (4 ml) was added to obtain a final pH of 0.33 for the remainder of the analysis, by reverse phase high performance chromatography (IIPLC). Test solubility results. All high-performance liquid are 3 in Table II.

Table II

Solubility of ASX in tablets prepared according to Example 2

Time (min) oh

Mean (n = 3) solubility,%

GO

120

130

210

1.0 i, o δ, 3

0.7 i

100.3

100.7

These tablets meet the criteria of USP / NF XVII for the enteric release of acetylsalicylic acid tablets (less than 10% by weight ASX is released after 120 minutes at ρΗ 1.0, more than 30% by weight is released after 9C minutes at pK 6 , 8).

The solubility of warfarin sodium is determined by placing the tablets in 900 ml of phosphate buffer pH 7.5 maintained at 37 ° C, while allowing the stirrer to rotate at 50 rpm. The diameter of the three tablets provides 91.3 wt. warfarin sodium released within 30 minutes, which complies with the specifications of USP / NF XVII (at least 80% by weight releasable within 30 minutes).

B. Enterioca coated ASX compressed into a multilayer tablet

This procedure serves to minimize the contact area of both drugs. The ASX particles, granules or granules are first coated with enterioca as specified in Ι-1Λ in the previous section. The enteric coated ASX is mixed with suitable excipients and warfarin sodium is dry granulated with the same excipients. The ASX mixture is then pressed and a layer of warfarin sodium is then pressed onto this layer. These two layers of both drugs make up a placebo. of this type.

is followed by an optional layer of the foot

Example 3

Component

Enteric coated ASK / warfarin sodium in a multi-layer tablet

Amount (mg) per dosage unit

ΑΞΧ coated with 9 to 25 wt. Eudragit ® L30D

Sodium perfararin

Laktoza

Sodium stearyl fumarate (tapioca) starch, pregelatinised

43.96 to 53.33 (40.0 mg active)

5.0

324.02 to 333.99 o, 0

3.05

Zelkem

400.0 mg

Prior to weighing, all components are passed through a suitable sieve as necessary. Weigh out all ingredients and combine warfarin sodium with one half of the manihotch starch and lactose.

Stir in a double-jacketed mixer for about 15 minutes.

Add one quarter of sodium stearyl fumarate and stir for about 3 minutes. This mixture was crushed using 1.27 cm flat blowers and ground. Add one quarter of sodium stearyl fumarate and stir for about 3 minutes. The ASK is mixed with the rest of lactose and mani-starch in a double-shell mixer and mixed for 10 minutes. The remaining sodium stearyl fumarate is added and mixed for about 3 minutes. Using a multi-layer tableting machine such as the Manestry Layer Press manufactured by Thomas Engineering, the ASM blend is compressed, followed by a granular warfarin sodium layer to give a two-layer tablet. It should be noted that the amount of lactose in the formulation thus formulated is adjusted to a total dose of 400 mg,

C. Enterioca coated tableted A3X in capsule

This form involves the production of A3X tablets or microtablets, which are then coated with enterioca and placed in a capsule together with granulated warfarin sodium, followed by an example formulation of a mixture of this type.

Example 4

Component

Enterioca coated ASK tablet mixed with warfarin sodium in a capsule

Amount (mg) per dosage unit

ASK (S)

Eudragit ^ L30D

Warfarin sodium

Laktoza

Microcrystalline cellulose

Dicalcium phosphate

Xroskarmeloza sodná

Xoloid silica gel

Hydrogenated vegetable oil

40.0

24.0

1.0

105.5

Π / O

134.5

15.0

1.0

12.0

Total 424.0 mg

Prior to weighing, all components are passed through a suitable sieve, if necessary. All components were weighed and the ASK was mixed with lactose, microcrystalline cellulose and one half of colloidal silica gel and croscarmellose sodium and mixed in a double-shell mixer for about 15 minutes. Add one half of the hydrogenated vegetable oil and mix for about 15 minutes,

This mixture is compressed into tablets which are coated with Eudragit® L30D by a suitable method known in the art, and arfarin sodium is mixed with dicalcium phosphate and the rest of colloidal silica gel and croscarmellose sodium for about 15 minutes. Add one quarter of hydrogenated vegetable oil and mix for about 5 minutes,

This mixture is beaten with 1.22 inch flat bumpers and ground. Add the remaining vegetable oil and stir for about 5 minutes. The formulated mixture is encapsulated using a capsule such as Zanasi AZ5 manufactured by the drawbar of Soteco L'5A, Ino by inserting

200 mg granulated warfarin sodium and one ASX tablet per capsule.

Example 5

Component

A mixture of tableted warfarin sodium / e coated with ASX in an eye capsule

Amount (mg) per dosage unit

ASX coated with 9 to 25 wt% Sudragit® L3CD

Warfarin sodium

Laktoza

Microcrystalline cellulose sodium starch glycolate Colloidal silica sodium sodium stearyl fumarate

Total

82.42 to 100.0 (75 mg active)

10.0

57.5 to 75.00 20.0 e, υ mg

Prior to weighing, all components are passed through a suitable sieve, if necessary. ASX is mixed with one half of lactose, sodium starch glycolate and colloidal silica gel and mixed for about 15 minutes in a double jacket mixer. One half of sodium stearyl fuma is added and mixed for about 5 minutes. The sodium perfarin is combined with microcrystalline cellulose and the remaining lactose, sodium starch glycolate and colloidal silica gel and mixed for about 15 minutes. Add one quarter of sodium stearyl fumarate and mix for about 4 minutes. This mixture was crushed using 1.27 cm flat bumpers and ground. Add the rest of sodium stearyl fumarate and mix for about 4 minutes. The granulated warfarin sodium is compressed into tablets. The formulation thus formulated is encapsulated in a capsule filling machine (eg Zanasi ΛΖ5), and one tablet with a sufficient amount of ASX is placed in the capsule to align the dosage unit in each capsule. It should be noted that the amount of lactose in the formulation thus formulated is adjusted to a weight of aspen dose of 200 my.

II. Sustained release of actdylsalicylic acid (ASK)

Sustained release with ASK part / warfarin sodium

These formulations include the coating of microtablets, particles, granules and grains with ASK material that permits continuous (R1 release, such as methacrylate ester copolymers (Eudragit® NE30O, Eudragit® RS30D and / or Eudragit® RL30D, Eudragit®)

RL and / or Eudragit® RS, all available from Rohm Pharma), organic-based cellulose ethylcellulose, aqueous-based ethyl cellulose (Aquacoat®, EMC Corp .; Surelease®, Colorcon), or other suitable material known in the art, to achieve sustained release for 3 to 12 hours. These coated entities (entities) can additionally be coated once again with a low viscosity hydroxypropyl methylcaluloza layer to protect against breaking of the permanent layer upon compression. These microtablets, particles, granules or beads may optionally be additionally coated with an enteric releasing polymer such as Acuater;

, Eudragit® L30D or Eudragit®

L and / or Eudragic S to achieve sustained release only in the intestine. Another way is to use a combination of polymers (such as Eudragit® IJE30D and Eudragit® L30D) in a single coating to obtain sustained release in the intestine. These layers can be applied in a fluidized bed, co-phase phase separation, bath coating, solid processes, or other suitable methods known in the art. The coated ASK is then mixed with suitable excipients and mixed with warfarin sodium granules and either placed in capsules or compressed into tablets. Similarly, the sustained release ASK blend may be compressed into tablets or micro-tablets, which may optionally be protected once more with an enteric layer coating, and placed in capsules along with granulated sodium warfarin. The two mixtures can also be used as in the manufacture of multi-layer tablets with ASK and warfarin sodium, in which the layers are separated.

This modification yields products that release ASK permanently.

In addition, contact between Λ3Κ and warfarin sodium in the product is minimal. The following is an example of a formulation of this type.

ι υ

Example 5 Sustained release of the ASX / warfarin sodium mixture

Component

Amount (mg) per dosage unit

% Of ASX coated with 3 to 15 wt. of ©

Surelease (Ethicellulose)

Warfarin sodium Microcrystalline cellulose sodium starch glycolate Colloidal silica gel Sodium stearyl fumarate

154.95 to 133.24 (150.0 mg active)

5.0

134.75 to 203.05

15.0

1,0 .xem

403.00 m;

Before weighing, all components are sieved on a suitable sieve. Sustained-release ASX, coated, one-half microcrystalline cellulose, colloidal silica gel and sodium starch glycolate are placed in a double-shell mixer and mixed for about 15 minutes. Sodium warfarin is combined with the remaining microcrystalline cellulose, colloidal silica gel and sodium starch glycolate and stirred for 15 minutes. Add half of sodium stearyl fumarate to the sodium wafarin mixture and stir for about 3 minutes. This mixture is beaten with 1.25 cm flat beating and artificial. The ASX mixture is combined with granulated sodium warfarin and mixed for about 10 minutes in a double-shell mixer. The remaining sodium stearyl fumarate is added, stirred for about 3 minutes, and the mixture is either compressed into tablets or placed in capsules. It should be noted that the amount of microcrystalline cellulose should be adjusted to a total of 403.0 mg.

Example 7 Sustained release of ASX compressed into tablets or microtablets / warfarin sodium in capsules

The components of Example 4 were used in equal amounts, which were sieved through a suitable sieve prior to binding.

A weighed amount of sustained release ASX, coated, and only half of the microcrystalline cellulose, sodium starch glycolate and colloidal silica gel are placed in a double-shell mixer and mixed for about 15 minutes. Half of the sodium stearyl fumarate is added and stirred for about 5 minutes. This mixture is compressed into tablets or microtablets. Sodium warfarin is combined with the remaining microcrystalline cellulose, colloidal silica gel and a quarter of sodium stearyl fumarate and mixed for about 15 minutes. This mixture was smashed using 1.25 cm flat beating and artificial. Add the remaining sodium stearyl fumarate and stir for about 5 minutes. Using a capsule filling machine such as Zanasi AZ5, the formulated mixture is encapsulated, wherein each capsule is loaded as a single dosage unit with an ASX tablet or micro-tablets and an appropriate amount of granulated sodium warfarin.

Example 3 Sustained release of ASX / warline arine from a multilayer tablet

Amount (mg) per dosage unit

% Of ASX coated with 3 to 15 wt. O

Surelease ^ (ethylcellulose) Warfarin sodium Microcrystalline cellulose sodium starch glycolate Xoloid silica gel Sodium stearyl fumarate

154.95 to 188.24 (150.0 mg active)

5.0

369.25 to 392.55

24.0

1.5

12.0

Total 600.00 mg

The components are sieved as necessary and weighed.

The sustained-release coated ASX and one half of the microcrystalline cellulose, sodium starch glycolate and colloidal silica gel are poured into a double-shell mixer and mixed for about 15 minutes.

Add two thirds of sodium stearyl fumarate and mix for about 5 minutes. Sodium warfarin is mixed with the remaining microcrystalline cellulose, sodium starch glycolate and colloidal silica gel and mixed for about 15 minutes. One sixth of sodium stearyl fumarate is added and mixed for about 5 minutes. The mixture is smashed using 1.2 74 cm flat beating and artificial. The remainder of the stearyl fumarate for the manufacture of multilayer tablets such as the Layer Press (manufactured by Thomas Engineering) is compressed with ASK followed by sodium warfarin granulate to form a bilayer tablet.

2. Sustained-release matrix tablet / warfarin sodium in capsule

In this formulation, a sustained release matrix tablet containing ASK is first produced by methods well known in the art. This tablet is placed in a capsule along with granulated sodium warfarin. Sustained-release matrices are obtained by mixing ASK with various types of hydroxypropyl methyl ether (IPI-IC) (Methoeel® K, Methocel® J, Kethccal® E, all manufactured phi)

Dow Chemical) and hydroxypropyl ethylcelluloses (Klucel, Dow Chemical), either alone or in combination, together with suitable excipients. When using listhocel K heaven • lethoc

% J having 2 wt. a viscosity of greater than 0.3 Pa.s, alone or a combination of both, the combined amount of lithium K and / or Methocel J should be greater than 25.3% of the total weight of the dosage form. If Methocel K or J or a combination thereof has 2¾ viscosities less than 0.3 Pa.s, then the hydroxypropyl content is less than 9% of the total weight of the dosage form. Alternatively, Methccel K and / or J may be blended with a cellulose ether other than HPMC cellulose, provided that the cellulose ether contains more than 30 wt. total polymer blends.

The matrix tablet may additionally be coated with a low-viscosity polymer (e.g., hydroxypropylmethylcaluloza) which acts in accordance with the polymer within the matrix to provide sustained release.

In all cases, drug release occurs for about 3 to 12 hours. The sustained release tablet is then placed in a capsule together with the warfarin sodium granulate. The ASK tablet can be coated according to known methods with an ethereal coating

- 1!

mater

Aquat Ialem, © eric,

6) ja.no ge Eudragit® L30D, or other materials well known. The result of this choice is only in the intestine.

. . ©

Suoragiu gauzes 3sou in achieving UUC: and _g © it the art, sustained release

Example Continuously release sodium in a capsule tablet / warfarin capsule

Component

Amount (mg) per dosage unit

Acstylsalicylic acid (AS? :) Methocel® L4M Premium CR Warfarin sodium

Lactose

Dicalcium phosphate

Colloidal silica gel

Sodium stearyl fumarate

150.0

103.95

2,0

123.07

125.32

2.3 4 12.32

Total

540.0 mg

100 ALIGN! 03032004, 10:13:19 Before the binding, all the components shall be sieved as necessary with a suitable sieve. The ASX is mixed with lactose, Methooel® and half colloidal silica gel and mixed for about 15 minutes in a double-shell mixer. Two-thirds of sodium stearyl fumarate is added and mixed for an additional 5 minutes. This mixture was compressed into tablets (135.77 mg each). The three tablets provide a sufficient amount of ASX per dosage unit (150 mg total ASK).

Sodium warfarin is mixed with dicalcium phosphate and the remaining colloidal silica gel for about 15 minutes. Add one sixth of the sodium stearyl fumarate and mix for about 5 minutes. This mixture was crushed using 1.27 µm flat bumpers and ground.

The remaining sodium stearyl fumarate is added and mixed for a further 5 minutes. This formulation is encapsulated by placing in each capsule a sodium warfarin granulate in an amount equal to one dosage unit and three ASX tablets. A capsule filling machine such as the Zanasi AZ5 is used.

According to this formulation (3, 4 < 4 >

SCO), a tableted component of ASX is produced and examined for drug release. Using the same equipment and medium as described in Example 2, except that 500 ml of C, 1 H HCl are used for the first two hours, the pH is adjusted to 7.5 by adding 250 ml of 1M sodium phosphate. . The solubility data are shown in Table III below.

Table III

Release of ASX from matrix tablets produced according to Example 9

PH time (hours)

Mean (n = 3) S release

1.0 1.0

7.5

7.5

7.5

7.5

75.5

34.7

95.2

If ASKs are included in the above examples with non-acetyisalicylic acid NSAIDs, ticlopidine, thromboxane receptor antagonists, or thromboxane synthetase inhibitors, other formulations may be prepared which are within the scope of this invention. In addition, in the above examples, warfarin can be replaced by other oral anticoagulants such as coumarin derivatives / for example phenindione, bis-hydroxycoumarin (dicoumarol) and phenprocoumarone] to formulations within the scope of the invention.

The increased efficacy and safety of the combination of a small dose oral anticoagulant, such as warfarin, with platelet aggregation and adhesion-inhibiting agents, also used at low dose, or with non-steroidal anti-inflammatory agents, particularly ASK, is supported by previous clinical experience with using the community of said or related compounds individually in high doses to prevent and treat acons

Z2 of three published, treatment of acute myocardial coronary ischemic syndromes and ischemic cerebrovascular disease, as well as some suggestive evidence from their current use.

Clinical studies using oral anticoagulants alone, including crystalline warfarin sodium, have shown their efficacy in the treatment or secondary prevention of coronary arterial disease.

randomly selected infarction control trials in one study showed that an oral anticoagulant significantly reduced the overall mortality and frequency of a new heart attack.

Of the four large-scale, randomly selected control trials of oral anticoagulants in the secondary prevention of myocardial infarction, three suggested that the possibility of new infarction and premature death was reduced. Another study of the Warfarin Reinfarction Study also recently demonstrated a significant reduction in mortality, re-infarction and seizures in people who had previously had a myocardial infarction and were treated with warfarin compared to people receiving piacebo.

Studies using azetylsalicylic acid (ASK) alone to prevent and treat coronary arterial disease were also promising. ^: AS patients with unstable angina pectoris have been shown to reduce the incidence of myocardial infarction and mortality with ASC. This finding was obtained by two large, randomly selected, double-blind and placebo-controlled clinical trials. In addition, ASK has been approved for use in the secondary prevention of myocardial infarction based on data from numerous trials which, after summarizing the knowledge, have concluded that ASK reduces the possibility of further heart attack and mortality. Finally, two recent studies evaluating ASC in the primary prevention of coronary arterial disease show either dramatic or subsequent improvement; ASK has not yet been approved for this indication.

In addition to being useful in the treatment of coronary arterial disease, agents that inhibit platelet aggregation and adhesion, such as ASK and thioiopidine, are effective in preventing seizures in people suffering from cerebrovascular disease. The data collected from nine random trials provide overwhelming evidence of the efficacy of ASC alone in reducing the risk of complete cerebral seizure in people suffering from transient ischemic attacks.

Recently, it has been shown that ticlopidine used alone also exhibits effects in the treatment of complete ischemic brain attack.

The assumption that ASK and warfarin in combination will have more beneficial effects than both agents individually is based on the latest angioscopic data and is supported by pivotal studies. To direct observation of the ulcerated. atherosclerotic plaques in coronary arteries are suggested by Forrester et al. two different pathological cycles of injury, due to agglomeration and adhesion and thrombi, and suggest a remedy for acute coronary ischemic syndromes, which clearly indicates the benefit of using both agents when applied in combination. This pathophysiological pattern can also be extrapolated to the cerebrovascular system. Recent data on patients with unstable angina pectoris show that it is preferable to receive both heparin (anticoagulant) / warfarin and ASK, as compared to patients receiving only one of the two drugs. In addition, patients with prosthetic heart valves receiving concomitant medication to prevent a seizure may be seen to have a noticeably lower incidence of myocardial infarction.

There is a need for a therapeutic approach to acute coronary ischemic syndromes and ischemic cerebrovascular diseases that takes into account the various pathophysiological forms of these diseases and involves the administration of agents that improve each of these pathophysiclogical components. A combination product containing a small dose of warfarin and a small dose of a platelet aggregation and adhesion inhibiting agent, such as a non-steroidal anti-inflammatory agent, and in particular rASK, may represent such an approach. In addition, the administration of small doses of each agent significantly reduces the incidence of gastrointestinal bleeding and other side effects accompanying the concomitant administration of these drugs at high doses and patients. administration of the two medicaments. It is generally accepted that better drug delivery results in greater patient satisfaction. In addition, the combination product, which can only be obtained by prescription, provides the physician with a greater ability to control the dose than if the patient independently selected one of the different doses and one of the formulated formulations. The combination products of the present invention also reduce the possibility of confusing the patient, often associated with the concurrent dosing of other medicaments when the combination product is unavailable.

Claims (14)

Pharmaceutical compositions for the prevention and / or treatment of a myocardial infarction or stroke in a mammal, comprising a pharmaceutical carrier and active compound combinations comprising an anticoagulant component of warfarin or a salt thereof, present in an amount of 0 , 5 to 10 mg, and an inhibiting blood clotting and adhesion function selected from the group consisting of: a) acetylsalicylic acid contained in an amount of 10 to 500 mg, b) piroxicam in amounts of 5 to 50 mg, C) indomethacin obsa 2 3 to 100 ALIGN! (d) naproxen contained in a feed amount of 20 to 1G0 -tg, '3) droxicam contained in an amount of 23 to 23 100 ALIGN! mg, f) diclofenac in a dosage amount of 20 to 100 mg; g) sulfinpyrazone contained in an amount of 20 to 100 mg; and n) ticlopidine comprised in an amount of 100 to 750 mg. Pharmaceutical compositions according to claim 1, characterized in that they comprise an anticoagulant component coated with a polymer and an agent which inhibits the clotting and adhesion functions of blood coated with an enteric-release polymer selected from the group comprising cellulose acetate phthalate; and (b) a methacrylic acid copolymer or a sustained release polymer selected from the group consisting of (a) methacrylic ester copolymer, (b) ethylcellulose soluble in an organic solvent, c) ethylcellulose soluble in aqueous solvent, (d) hydroxypropylcellulose; (e) hydroxypropylethylcellulose; and f) hydroxypropylmethylcellulose, the warfarin polymer being hydroxypropylmethylcellulose, of which 2 wt. the solution has a viscosity of less than 2 Fa.s. Pharmaceutical compositions according to claim 1, characterized in that they are: · Oh as a burst inhibiting agent; and the blood adhesion functions include aootylsalicylic acid. Pharmaceutical compositions according to claims 1 and 3, characterized in that they contain warfarin in a releasable amount of 1 to 7.5 mg and acetylsalicylic acid in a releasable amount of 20 to 325 mg. Pharmaceutical compositions according to claim 4, characterized in that they contain acetylsalicylic acid in a releasable amount of 40 to 162.5 mg. Pharmaceutical compositions according to claim 3, characterized in that they comprise acetylsalicylic acid coated with enteric-releasing polymer. Pharmaceutical compositions according to claim 3, characterized in that they comprise acstylsalicylic acid coated with a sustained release material. Pharmaceutical compositions according to claim 7, characterized in that they comprise acetylsalicylic acid coated with a sustained release material and still enteric coated. Pharmaceutical compositions according to claim 1, characterized in that they contain piroxicam as a non-acetylsalicylic acid non-steroidal agent which inhibits the clotting and adhesion functions of blood. 10. Pharmaceutical compositions according to claim 1, characterized in that they contain indoraethacin as a non-acatylsalicylic acid non-steroidal agent which inhibits the clotting and adhesion functions of the blood. 11. Pharmaceutical compositions according to claim 1, characterized in that they are non-acetylsalioyl aestoroid Z. O naproxen inhibiting agent. clustering and adhering functions of blood content; 12. Pharmaceutical compositions according to claim 1, characterized in that they comprise, as a non-acetylsalicylic acid non-steroidal agent, inhibiting blood clotting and adhesion functions. C*. 2. The composition according to claim 1, wherein the non-steroidal non-steroidal non-steroid formulations are: 14. Pharmaceutical compositions according to claim 1, characterized in that they comprise sulfinpyrazone as a non-acetylsalicylic acid non-steroidal agent which inhibits the clotting and adhesion functions of the blood. 15. Pharmaceutical compositions according to claim 1, characterized in that they contain ticlopidine as a non-acetylsalicylic acid non-steroidal agent which inhibits the clotting and adhesion functions of the blood. Pharmaceutical compositions according to claims 1 and 15, comprising warfarin in a releasable amount of 1 to 7.5 mg and ticlopidine in a releasable amount of 2C0 to GOOmg, Pharmaceutical compositions according to claims 1 and 16, characterized in that they contain warfarin in a releasable amount of 1 to 5 mg and ticlopidine in a releasable amount of 2 to 500 mg. LJ. Pharmaceutical compositions according to claim 2, characterized in that they comprise an enteric-coated aostylsalicylic acid coated with a release polymer selected from the group consisting of cellulose acatate copolymers with phthalate or methacrylic acid. Pharmaceutical compositions according to claim 2, characterized in that they contain warfarin coated with hydroxypropyl methylcaluloza. 20 May Pharmaceutical compositions according to claim 2, feature- o i The composition of claim 1, wherein said coating comprises acetylsalicylic acid nou a sustained release polymer. 21. The pharmaceutical compositions of claim 2, 5 and 3, and - No. U characterized in that it is used as enterioc releasing polymer ObS · attract the methacrylic acid copolymer.